TY - JOUR

T1 - Interplay between base excision repair protein XRCC1 and ALDH2 predicts overall survival in lung and liver cancer patients

AU - Chen, Xin

AU - Legrand, Arnaud J.

AU - Cunniffe, Siobhan

AU - Hume, Samuel

AU - Poletto, Mattia

AU - Vaz, Bruno

AU - Ramadan, Kristijan

AU - Yao, Dengfu

AU - Dianov, Grigory L.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Background: To deliver efficacious personalised cancer treatment, it is essential to characterise the cellular metabolism as well as the genetic stability of individual tumours. In this study, we describe a new axis between DNA repair and detoxification of aldehyde derivatives with important implications for patient prognosis and treatment. Methods: Western blot and qPCR analyses were performed in relevant non-transformed and cancer cell lines from lung and liver tissue origin in combination with bioinformatics data mining of The Cancer Genome Atlas database from lung and hepatocellular cancer patients. Results: Using both biochemical and bioinformatics approaches, we revealed an association between the levels of expression of the aldehyde detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) and the key DNA base excision repair protein XRCC1. Across cancer types, we found that if one of the corresponding genes exhibits a low expression level, the level of the other gene is increased. Surprisingly, we found that low ALDH2 expression levels associated with high XRCC1 expression levels are indicative for a poor overall survival, particularly in lung and liver cancer patients. In addition, we found that Mithramycin A, a XRCC1 expression inhibitor, efficiently kills cancer cells expressing low levels of ALDH2. Conclusions: Our data suggest that lung and liver cancers require efficient single-strand break repair for their growth in order to benefit from a low aldehyde detoxification metabolism. We also propose that the ratio of XRCC1 and ALDH2 levels may serve as a useful prognostic tool in these cancer types.

AB - Background: To deliver efficacious personalised cancer treatment, it is essential to characterise the cellular metabolism as well as the genetic stability of individual tumours. In this study, we describe a new axis between DNA repair and detoxification of aldehyde derivatives with important implications for patient prognosis and treatment. Methods: Western blot and qPCR analyses were performed in relevant non-transformed and cancer cell lines from lung and liver tissue origin in combination with bioinformatics data mining of The Cancer Genome Atlas database from lung and hepatocellular cancer patients. Results: Using both biochemical and bioinformatics approaches, we revealed an association between the levels of expression of the aldehyde detoxifying enzyme aldehyde dehydrogenase 2 (ALDH2) and the key DNA base excision repair protein XRCC1. Across cancer types, we found that if one of the corresponding genes exhibits a low expression level, the level of the other gene is increased. Surprisingly, we found that low ALDH2 expression levels associated with high XRCC1 expression levels are indicative for a poor overall survival, particularly in lung and liver cancer patients. In addition, we found that Mithramycin A, a XRCC1 expression inhibitor, efficiently kills cancer cells expressing low levels of ALDH2. Conclusions: Our data suggest that lung and liver cancers require efficient single-strand break repair for their growth in order to benefit from a low aldehyde detoxification metabolism. We also propose that the ratio of XRCC1 and ALDH2 levels may serve as a useful prognostic tool in these cancer types.

KW - Aldehydes

KW - ALDH2

KW - Base excision repair

KW - DNA damage

KW - Genetic instability

KW - Liver and lung carcinomas

KW - Mithramycin a

KW - XRCC1

KW - Cell Line

KW - DNA Damage/genetics

KW - Humans

KW - RNA, Small Interfering/genetics

KW - Plicamycin/analogs & derivatives

KW - Cell Survival/drug effects

KW - Liver Neoplasms/genetics

KW - Lung Neoplasms/genetics

KW - X-ray Repair Cross Complementing Protein 1/antagonists & inhibitors

KW - Cell Line, Tumor

KW - Aldehyde Dehydrogenase, Mitochondrial/genetics

KW - DNA-DAMAGE RESPONSE

KW - MITHRAMYCIN

KW - ALDEHYDE DEHYDROGENASE 2

KW - POLYMERASE-BETA

KW - METABOLISM

KW - RECONSTITUTION

KW - CELLS

KW - MECHANISMS

KW - CONSEQUENCES

KW - ENDOGENOUS ALDEHYDES

UR - http://www.scopus.com/inward/record.url?scp=85051846099&partnerID=8YFLogxK

U2 - 10.1007/s13402-018-0390-8

DO - 10.1007/s13402-018-0390-8

M3 - Article

C2 - 30088263

AN - SCOPUS:85051846099

VL - 41

SP - 527

EP - 539

JO - Cellular oncology (Dordrecht)

JF - Cellular oncology (Dordrecht)

SN - 2211-3428

IS - 5

ER -